Neuropathic pain is a daily painful condition persisting at least 3 months and often

described as burning, squeezing, dull, deep aching, sharp, stabbing, jabbing, cramping, and
tingling. Some patients experience numbness; the affected area might also be much more
sensitive to various stimuli. Chronic neuropathic pain can be challenging to treat. Medications
are an important part of neuropathic pain management. A variety of pharmacologic agents,
including tricyclic antidepressants, local anesthetic derivatives, opioids, sympatholytics,
anticonvulsants, and novel agents such as calcitonin and baclofen have been found useful in
patients with neuropathic pain conditions1-10; however, many patients experience incomplete
pain relief with these agents or intolerable side effects requiring discontinuation of therapy.
Therefore, the search for alternative effective and safe therapies for the treatment of neuropathic
pain continues. Although the etiologies of neuropathic pain syndromes are varied, the underlying
pathology seems to include some abnormal activation of neurons within the nociceptive
system.11 Animal models of peripheral nerve injury at the root level or more distal sites show
spontaneous activity in damaged nerve segments, mechanical sensitivity, and evidence of
involvement of the sympathetic nervous system.12-14 Therefore, medications that reduce
excessive discharge from pathologically altered neurons would seem to be good choices for
management of neuropathic pain syndromes.
Clonidine, an α2-adrenergic agonist active in dorsal horn and brainstem, has been shown
to produce analgesia and has played an important role in the control of acute and chronic
pain.4,15-18 It is administered by transdermal, intravenous, oral, and epidural routes to suppress
central ner-Tizanidine in Neuropathic Pain vous system (CNS) noradrenergic activity and
peripheral sympathetic tone. However, clonidine frequently causes significant hypotension,
bradycardia, and sedation, which often limit its use. Tizanidine is a central α2-adrenoreceptor
agonist that is structurally related to clonidine.19 Data suggest that tizanidine has numerous
pharmacologic properties, including reduction in the release of excitatory amino acids and
substance P in polysynaptic pathways, postsynaptic reduction in excitatory transmitter activity,
and inhibition of the synaptic transmission of nociceptive stimuli in the spinal pathways.15-
17,19-21 Animal studies have shown that intrathecal tizanidine provides antinociception without
producing pronounced hemodynamic changes.16,17 There have been no clinical trials published
to date that have examined the potential role of oral tizanidine in the treatment of neuropathic
pain. Therefore, a prospective evaluation was carried out at the Outpatient Neurology Clinic of
the University of Arizona Medical Center in Tucson, AZ, to examine the effectiveness and side
effect profile of oral tizanidine in the treatment of neuropathic pain.

The clinical application of tizanidine for the palliation of painful conditions has been in
practice in Europe and Japan for more than 12 years. Specifically, double-blind placebo-
controlled clinical trials have shown that tizanidine is useful in acute back pain as well as
tension-type headache. 24-27 The effective pain-relieving dose of tizanidine reported in these
studies ranged from 6 mg/day to 24 mg/day with response rates being statistically significant in
favor of tizanidine compared with placebo. There is, to our knowledge, no available literature on
the effect of tizanidine for painful neuropathic conditions. The results of this openlabel trial offer
preliminary evidence that tizanidine, at a mean dose of 23 mg/day, might be clinically effective
for the treatment of neuropathic pain. Of the patients treated in the trial, two thirds reported that
their pain was improved or much improved with tizanidine. Two of these patients became
completely painfree. Although oral clonidine, also an α2-adrenergic agonist, had not been tried
in the study patients, oral tizanidine might prove to be a unique and valuable agent for the
treatment of neuropathic pain. The current standard of treatment for patients with neuropathic
pain is oral adjuvant analgesics such as tricyclic antidepressants, anticonvulsants, and
antiarrhythmics/anesthetics. However, tremendous individual variability has been shown in
response to the different pharmacologic agents, even among patients with the same clinical
diagnosis. For example, a number of patients enrolled in this study had tried unsuccessfully
multiple other agents including amitriptyline and gabapentin; however, they obtained pain relief
with tizanidine. Research has found that neuropathic pain conditions typically are caused by
multiple mechanisms.28,29 Therefore, optimal treatment might require several drugs with
different mechanisms and sites of nervous system activity to achieve the best possible clinical
response. The mechanism of action of tizanidine in the treatment of neuropathic pain remains
uncertain. Inhibition of the synaptic transmission of nociceptive stimuli in the spinal pathways
might mediate this effect. Neuropathic pain typically arises as a result of trauma or disease to
neurons; this, in turn, leads to hyperexcitability of the neurons particularly in the sympathetic
system. Patients in this study were not specifically screened for sympathetically maintained
neuropathic pain, and they had not been tried previously on clonidine, which has shown an
antiallodynic effect for sympathetically maintained pain.30 Nevertheless, the proposed inhibitory
action of tizanidine on the neurons appears quite plausible. Inhibition of the release of aspartic
and glutamic acid and substance P, which have all been implicated in the pathophysiology of
neuropathic pain, also might be responsible for tizanidine’s efficacy. A variety of different
qualities of neuropathic pain, including sensations of being intense, sharp, hot, dull, cold,
sensitive, unpleasant, and deep, responded to tizanidine administration. It has been suggested that
different pain descriptors might reflect different underlying pain mechanisms.31 If correct,
tizanidine might have broad utility in various pain conditions, given its demonstrated ability in
this study to diminish multiple different pain sensations; however, additional research is needed.
The lack of treatment effects of tizanidine on itchy and surface pain might be caused, at least in
part, by the fact that subjects had minimal complaints of itchy and surface pain at the start of the
trial.
Quality of life assessments indicated that the majority of patients had better health,
functioning, and enjoyment of life ratings after treatment with tizanidine. This is an extremely
important measure of clinical benefit given the staggering societal and health-related costs
associated with poorly treated chronic pain. Although dizziness and lightheadedness were
frequently reported upon initiation of tizanidine,orthostatic hypotension, which is common with
other α2 agonists such as clonidine, was not observed. Compliance problems did not occur as a
result of these symptoms, and patients noted a lessening, and often resolution, of the dizziness/
lightheadedness with continued tizanidine use. Slower dose titration of tizanidine might
eliminate the emergence of dizziness and lightheadednesss. Drowsiness and fatigue also were
commonly reported; however, many patients had sleep difficulty caused by their neuropathic
pain, making these effects advantageous. It should be noted that elevation in LFTs has been
reported with tizanidine. In well-controlled clinical studies, approximately 5% of patients treated
with tizanidine had elevations of LFTs to greater than 3 times the upper limit of normal
compared with 0.4% in the control patients.32 Most cases resolved rapidly upon drug withdrawal
with no reported residual problems. Such was the experience with one of the patients in this
study. The two other patients with mildly elevated LFTs had a return to within normal limits
while on tizanidine, making it difficult to establish an exact cause/effect relationship. For
example, usage of multiple other medications by the study patients might have contributed to the
elevation observed. The manufacturer recommends that LFTs be ascertained at initiation of
tizanidine therapy, then again at 1, 3, and 6 months, and periodically thereafter. These guidelines
should certainly be adhered to when tizanidine is prescribed given the elevations that were
observed in this trial. The major limitations of this study are the small sample size and its open
design, as placebo response rates in pain conditions can be high. Without a placebo comparator,
the current study’s findings should be viewed as preliminary results that need to be confirmed in
a randomized, double-blind, placebo-controlled study.

The results of this small uncontrolled pilot study suggest that tizanidine, at a mean dose
of 23 mg (range 6 to 36 mg) might be an effective treatment for neuropathic pain. Inhibition of
the synaptic transmission of nociceptive stimuli in the spinal pathways might mediate this effect.
Placebo-controlled trials of tizanidine should be sought. In addition, comparative studies with
alternative agents such as other α2-adrenergic agonists, tricyclic antidepressants, and
anticonvulsants are warranted.
 This systematic review identified six small double-blind randomized trials (including five
cross-over trials) investigating the effects of muscle relaxants on pain management in patients
with A. Five trials assessed a benzodiazepine (four trials diazepam, 71 participants; one trial
triazolam, 15 participants) and one trial used the non-benzodiazepine agent zopiclone (40
participants). Four trials were placebo controlled and two were the benzodiazepine in
combination with an NSAID against an active NSAID comparator. All of the trials were deemed
to have a high risk of bias. No trial was longer than two weeks duration with 50%of the included
trials being single dose studies. No benzodiazepine trial was longer than one week in duration.
No study reported the primary outcome measure of patient reported pain relief of 30% or greater.
When pooled, the short term single dose studies assessing diazepam showed no benefit over any
of the control arms. When compared with placebo, studies assessing pain outcomes at 24 hours
had conflicting results. One small, single dose study of inpatients reported a significant benefit of
a single dose of diazepam over placebo in improving night pain (Bayley 1976). Patients had a
modest mean improvement of only 0.9 cm on a 10 cm VAS (95% CI 0.03 to 1.77), which is of
questionable clinical significance. In this study there was no benefit of a single dose of diazepam
over indomethacin in reducing pain levels in inpatients with RA (Bayley 1976). Similarly, there
was weak evidence from two small single dose cross-over studies that there was no additional
benefit on pain reduction from adding a benzodiazepine to regular NSAID treatment versus
NSAID treatment alone (Hobkirk 1977; Sharma 1978) in inpatients with active RA. Three
studies evaluated muscle relaxants over one to two weeks and found no benefit over placebo
(Drewes 1998; Vince 1973; Walsh 1996). Pooling of these trials showed no significant
improvement in mean pain levels. Reliable conclusions about comparative withdrawals due to
adverse events and the total adverse event rates could not be drawn from these short trials. Abuse
and addiction were not evaluated and no serious adverse events or deaths were reported. Only
one of the three trials comparing a benzodiazepine with placebo reported withdrawals due to
adverse events and the event rate in this single dose trial was zero (Bayley 1976). In the other
two single dose combination studies, there was one event only in each trial (Hobkirk 1977;
Sharma 1978). There were no withdrawals due to adverse events after two weeks of treatment in
the single study of zopiclone. Overall, 34% of patients receiving an intervention and 22% of
patients in the control groups suffered an adverse event. When pooled over all time periods, there
was only a trend towards an increase in adverse events in patients receiving muscle relaxants
(RR 1.40, 95% CI 0.58 to 3.41). Not surprisingly, the rate of adverse events for diazepam varied
greatly between the single dose trials (11% to 28%) and the two week study (71%). When data
from the trials of more than 24 hours duration were pooled there were significantly more adverse
events (NNTH 3, 95% CI 2 to 8). Consistent with the literature, these were predominantly central
nervous systemside effects, including dizziness and drowsiness (NNTH 3, 95% CI 2 to 11). In
the one small trial of zopiclone, 32%suffered an adverse event with 14%of events related to
dizziness and drowsiness. Given the small sample size there was only a trend towards
significance (RR 14.04, 95% CI 0.87 to 227.89). No trials with benzodiazepines reported
functional status as an outcome. One benzodiazepine trial measured quality of life and
depression and reported no significant difference for either of these after one week (Walsh
1996). The non-benzodiazepine trial showed no difference in HAQ scores after two weeks but it
did not measure quality of life or depression (Drewes 1998). There was weak evidence of no
short term improvement in any subjective sleep outcomes in the small, single dose trials of
patients taking benzodiazepines when compared with placebo, NSAID, or in combination with
an NSAID (Bayley 1976; Hobkirk 1977; Sharma 1978).Objective and subjective improvements
in sleep latency, total sleep time and the number of awakenings were seen after two weeks of
treatment in one trial evaluating triazolam(Walsh 1996). Daytime sleepiness was, however, no
different than for those receiving placebo. In the one non-benzodiazepine trial, there was a
positive effect on the subjective assessments of some sleep parameters (sleep latency, frequency
of awakenings) however objective sleep outcomes were not significantly different (Drewes
1998). In this trial, despite the improvements in subjective sleep ratings, clinical parameters such
as pain, morning stiffness and sleepiness remained unaltered.

Overall completeness and applicability of evidence

There were many limitations of this review. There were no large trials, limited head-to-
head trials and no studies of longer than two weeks duration. There was also a lack of data on
many commonly used benzodiazepine agents (alprazolam, clonazepam, lorazepam, oxazepam
etc.) as well as no available data on any of the skeletal muscle relaxants. Physicians are also
often concerned about the potential problem of addiction and withdrawal associated with these
agents, however no study addressed these outcomes so no conclusions can be made in regards to
this in this patient population. The populations included in this review are not reflective of
current day patients with RA. More than half the included trial participants were inpatients who
were hospitalised with poorly controlled disease. Many were only receiving NSAIDs, or
occasionally low dose corticosteroids or DMARDs, reflective of practice at the time. The
patients selected for inclusion were predominantly women and had various degrees of RA
disease severity. It was unclear what other analgesics they were taking at the time of the studies
and whether the patients had any co-morbidities. It also remains unclear as to what type of pain
these agents were being used for. The nature and duration of the pain and whether any other
analgesics were being used (or were no longer needed) were not described in any of the studies.
No trial reported the primary efficacy outcome measure of patient reported pain relief of 30%
or greater. The mean changes reported were often small and even though statistically significant
they may not have been clinically significant. Functional status, subjective and objective sleep
outcomes, depression and quality of life data are known to be important outcomes in this patient
population, and any information regarding these outcomes were sparsely reported. Safety and
efficacy data are limited to a maximum of one week for the benzodiazepines and two weeks for
the only non-benzodiazepine included in this review (zopiclone). Reliable conclusions about
withdrawal due to adverse events and total adverse event rates can not, therefore, be drawn
fromthese short trials. Although not identified in our review, chlorzoxazone has been implicated
in the development of serious (including fatal) hepatocellular toxicity. Chlormezanone has also
been implicated in causing Stevens- Johnson syndrome and toxic epidermal necrolysis.
 Recent literature analyzing the prevalence of muscle relaxant use is scarce. Some
clinicians would agree that the medications in this class tend to be used more frequently than
necessary, but clear data are lacking. IMS Health data from 2003–2004 showed carisoprodol,
cyclobenzaprine, and metaxalone accounted for more than 45% of all prescriptions written for
the management of musculoskeletal pain.9 Dillon et al. sought to define U.S. usage patterns
using data from the third National Health and Nutrition Examination Survey (NHANES III).10
In this cross-sectional prevalence study, the authors concluded that approximately two million
U.S. adults used skeletal muscle relaxants. Interestingly, the study found that although two-thirds
of patients taking these agents had a recent history of back pain, the prevalence of these
medications was only 4% among all participants who reported a history of back pain in the
previous year (95% CI, 2.9%–5.2%). In addition, the study showed that 44.5% of users took
muscle relaxants for more than a year (95% CI, 35.7%–53.3%). This finding is of concern
because each agent is recommended only for short-term use and has yet to be studied in chronic
management. Sociodemographic analysis of the data shows users’ median age was 42.3 years
(95% CI, 38.1–47.8), and 16% were more than 60 years old.10 While the findings in this study
offer some data on muscle relaxant use, it is important to remember that the NHANES III survey
presents information from 1988 to 1994. A systematic review indicated that skeletal muscle
relaxants were effective in the short-term relief of acute low back pain when compared with
placebo.6 However, these agents were associated with a 50% increased risk of adverse events
(AEs) with a relative risk of 1.50 (95% CI, 1.14–1.98).6 Specifically, central nervous system
(CNS) adverse events had a stronger association with skeletal muscle relaxant use, with a
relative risk of 2.04 (95% CI, 1.23–3.37).6 In addition to sedation, patients may experience
headaches, blurred vision, and dependency with the use of these agents.

There are very few high-quality studies comparing the efficacy of skeletal muscle
relaxants.6 Only one high-quality head-to-head study shows superiority of carisoprodol to
diazepam.11 Additionally, no studies have been conducted to valuate skeletal muscle relaxants
compared with first-line treatments (e.g., acetaminophen or NSAIDs). Therefore, if a skeletal
muscle relaxant is needed, an appropriate selection should be based on individual factors
including duration and severity of symptoms, prior response to medications, potential side
effects, desired benefits, comorbid conditions, and cost.5,6 One element of selecting the correct
treatment involves ensuring that the agent is used in appropriate populations. The Beers Criteria
for Potentially Inappropriate Medication Use in Older Adults is a collection of recommendations
from health care providers on medications with potential AE risks that outweigh most benefits
for use. Because they cause CNS depression, several skeletal muscle relaxants are on the Beers
list, including carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, and
orphenadrine.12 These agents are poorly tolerated in patients more than 65 years old due to
anticholinergic AEs, sedation, and risk for falls and fractures.12 Despite this risk, approximately
15% (300,000) of annual prescriptions for skeletal muscle relaxants are given to patients over the
age of 65.10 In a nationwide case-control study in the Medicare Advantage population, the use
of skeletal muscle relaxants was associated with a 40% increase in fracture risk (adjusted odds
ratio [OR] = 1.40; 95% CI, 1.15–1.72, P < 0.001).13 Furthermore, the risk increased with the
concomitant use of long-acting benzodiazepines (adjusted OR = 2.66; 95% CI, 1.94–3.65).13
Although this study was retrospective, the results support the classification of these agents on the
Beers list. Billups et al. conducted a pre-post cohort analysis to compare the incidence of
physical injury in patients before and after the initiation of a skeletal muscle relaxant. Although
retrospective in design and with limitations, this study showed a small, statistically significant
increase in injury including fractures, contusions, lacerations, and falls within the first 60 days of
initiation of a skeletal muscle relaxant.14 These results do not imply that use should be avoided
in all geriatric patients but suggest clinicians should be cautious, personalize therapy, and assure
that the benefits outweigh the risks of side effects. When considering the overuse of these
medications, it is important to understand the consequences and possible dangers to the public.
The Substance Abuse and Mental Health Services Administration and the U.S. Department of
Health and Human Services released national estimates of drugrelated visits to hospital
emergency departments (EDs) based on data from the Drug Abuse Warning Network (DAWN),
a public health surveillance system of non-federal hospitals operating 24-hour EDs. Participating
hospitals retrospectively review cases involving all types of drug use, including illegal,
prescription, and over-the-counter medications. Estimates are made each calendar year, allowing
for comparisons between years that show changes in prevalence among the different classes of
medications. In the 2011 DAWN update, 33.9% of the ED visits from anxiolytics, including
benzodiazepines, were associated with nonmedical use of prescription drugs.15 Even though the
prevalence is lower than other agents such as analgesics, skeletal muscle relaxants are still a
major concern in the U.S. In 2011, an estimated 53,000 ED visits were caused by muscle
relaxant misuse or abuse, and 18% of these cases involved oncomitant alcohol consumption.15
Carisoprodol was the most common skeletal muscle relaxant misused, with 25,528 cases,
followed by cyclobenzaprine with 11,551 cases, contributing 2.1% and 0.9%, respectively, of all
visits involving nonmedical use of pharmaceuticals.15 When investigating rates of suicide
attempts, muscle relaxants were the primary agent in 4.8% of cases.15 Cyclobenzaprine was the
most common agent (2.5%), followed by carisoprodol (1.0%). Since 2004, there has been an
84% increase in skeletal muscle relaxant involvement in suicide attempts, with cyclobenzaprine
accounting for more than half of such visits.15 In an effort to investigate the potential shift in
abuse or misuse of agents after carisoprodol was reclassified as a controlled substance, a search
was conducted on skeletal muscle relaxant exposures reported to the Florida Poison Information
Center Network from 2009 to 2012. Data extracted included intentional abuse or misuse of
carisoprodol, cyclobenzaprine, and a combination of other muscle relaxants. The frequency
of carisoprodol exposure in 2012 after its reclassification as a controlled substance was 75 cases,
compared with an average of 132 cases annually between 2009 and 2011.16 Interestingly, the
frequency of cyclobenzaprine exposure decreased to 27 cases in 2012 compared with an average
of 36 cases annually between 2009 and 2011.16 Data on other muscle relaxant exposures
showed variation among years without a clear increase in abuse or misuse after carisoprodol
became a controlled substance.16 Additional analysis must be done to assess the impact of the
reclassification of carisoprodol on the frequency of misuse and abuse of other, noncontrolled
skeletal muscle relaxants
INTRODUCTION
Muscle relaxants can be divided into 2 groups: antispastics and antispasmodics.
Antispastics (baclofen, dantrolene) are prescribed for spastic neurologic conditions such as
cerebral palsy and multiple sclerosis. There is no evidence that these agents are useful for acute
painful musculoskeletal conditions and should not be used for such. Antispasmodic agents which
are used for acute painful musculoskeletal conditions are divided into 2 groups: benzodiazepines
and non-benzodiazepines. The non-benzodiazepines include cyclobenzaprine, tizanidine,
carisoprodol, metaxolone, and methocarbamol among others (1,2). While the mechanism for
most of these agents is unclear, they are all central nervous system depressants and their effect
may be related to sedation. Cyclobenzoprine (flexeril) is related to tricyclic antidepressants.
Methocarbamol (robaxin) is structurally similar to mephenisin, and while the mechanism of
action is unknown, it is thought to cause inhibition of carbonic anhydrase and may interact with
NMDA receptors. Tizanidine (zanaflex) is a centrally acting alpha-2 receptor agonist.
Antispasmodics have been utilized for quite some time in the treatment of acute musculoskeletal
low back pain. These agents have gained recent popularity for inclusion in multimodal pain
management strategies for treatment of acute pain despite the limited evidence demonstrating
efficacy for these agents. The following review is of the agents used most frequently in
multimodal pain management strategies.

LITERATURE REVIEW

Cyclobenzaprine

In 2001, Browning et al. evaluated cyclobenzaprine in the treatment of acute low back
pain (3). This was a meta-analysis involving 14 randomized controlled trials. This meta-analysis
found that compared to placebo, those patients given cyclobenzaprine were more likely to report
improvement of symptoms at day 14 compared to those given placebo (Odds ratio 4.7, 95% CI
2.7-8.1). The treatment effect was modest (0.38-0.58) but was observable in all 5 investigated
outcomes: local pain, muscle spasm, tenderness to palpation, range of motion, and activities of
daily living. Efficacy was greatest in the first 3 days of treatment and declined over the next 1 to
2 weeks. The number needed to treat for 1 improvement was 3 patients. Adverse effects were
more likely in the cyclobenzaprine group and included drowsiness, dizziness, and dry mouth.
The authors noted that most of the studies included in the analysis had significant limitations
including inadequate blinding, inadequate description of randomization, inadequate description
of selection/inclusion criteria, etc… In 2003, Turturro et al. conducted a small randomized trial
in patients presenting to the emergency department with minor trauma and acute musculoskeletal
pain (4). In this trial, patients were randomized to ibuprofen plus cyclobenzaprine vs. ibuprofen
alone for 48 hours following presentation. At no time throughout the study did the addition of
cyclobenzaprine result in a significant improvement in reported pain score over ibuprofen alone.
However, the cyclobenzaprine group did show an increase in central nervous adverse effects
including sedation, light headedness, fatigue, and confusion. In 2015, Friedman et al. performed
a randomized controlled trial in patients presenting to the emergency department with acute low
back pain (5). All patients received naproxen and were randomized into 3 other protocols:
placebo, cyclobenzaprine, and oxycodone/acetaminophen. Patients were treated as outpatients
for one week and re-evaluated at the end of this period using the Roland Morris Disability
Questionnaire (RMDQ). At one week follow up, the RMDQ improvement in the placebo group
was 9.8, in the cyclobenzaprine group was 10.1, and in the oxycodone/acetaminophen group was
11.1. Between group difference in mean RMDQ improvement for cyclobenzaprine vs. placebo
was 0.3 (98.3% CI, -2.6 to 3.2; p=0.77), for oxycodone/acetaminophen vs. placebo was 1.3
(98.3% CI, -1.5 to 4.1; p=0.28), and for oxycodone/acetaminophen vs. cyclobenzaprine was 0.9
(98.3% CI, -2.1 to 3.9; p=0.45). They concluded that among patients with acute low back pain,
the addition of oxycodone/acetaminophen or cyclobenzaprine to naproxen did not improve pain
scores or functional outcomes at 1 week post-injury.

Methocarbamol
Methocarbamol is one of the oldest antispasmodics having been in use since the 1950’s.
While the exact mechanism of action is unclear, it is thought to act within the spinal cord and
inhibit muscle spasm without affecting the neuromuscular junction. In 1975, Tisdale performed a
double blind randomized controlled trial of methocarbamol vs. placebo in patients with acute
musculoskeletal pain and spasm from traumatic or inflammatory conditions (6). A total of 180
patients were randomized into either placebo or treatment groups. After 48 hours, they found that
there was a significant advantage in the methocarbamol group compared to placebo. After 48
hours, 76.7% of methocarbamol patients reported improvement in local pain compared to 42.2%
in the placebo group. Muscle spasm and limitation in motion was reported as improved in 75.6%
and 72.2% compared to 43.3% and 56.7%. Finally, 81% of patients in the methocarbamol group
reported that they would take the medication again for a similar condition compared to 47% of
placebo patients. In 2005, Hidalgo et al. investigated the use of methocarbamol in a breast
augmentation model (7). This trial was conducted in 2 phases. In the first phase, all patients
received preoperative oral methocarbamol and were randomized to receive intercostal nerve
blocks or no nerve blocks. In the second phase, patients did not receive any methocarbamol, but
were still randomized to receive intercostal nerve blocks or no nerve blocks. This group found
that whether or not a patient received intercostal nerve blocks had no impact on VAS pain
scores, but use of methocarbamol was associated with lower VAS pain scores in the first 6 hours
after surgery. There was no benefit beyond this time frame. Postoperative narcotic use was not
different among the 4 groups. In 2013, Looke et al. performed a retrospective review of 150
patients receiving primary hip and knee replacement surgery (8). These patients were given
intravenous methocarbamol and acetaminophen in the preoperative area. These were compared
to 150 historical controls who received preoperative oral analgesics including oral oxycodone,
acetaminophen, and pregabalin. Compared to the group receiving preoperative oral analgesics,
the group receiving IV acetaminophen and methocarbamol showed significantly less
postoperative opioid use and improved physical therapy progress with increases in average and
maximum walking distance. Finally, in 2015 Aljuhani et al. performed a retrospective matched
cohort study of 100 patients receiving methocarbamol for 3 days following admission for
traumatic injury (9). They found that there was no significant association between
methocarbamol use and mean pain score on day 1 [coefficient 0.09, 95% confidence interval
(CI), 20.57 to 0.75, p = 0.782, model R2 = 0.43], day 2 (coefficient 0.47, 95% CI, 20.15 to 1.09,
p = 0.140, model R2 = 0.42), or day 3 (coefficient 0.51, 95% CI, 20.13 to 1.16, p = 0.117, model
R2 = 0.42) after injury. They concluded that methocarbamol did not improve pain control in the
first 3 days of admission following traumatic injury.

Tizanidine
Tizanidine is a centrally acting alpha-2 adrenergic agonist. In 1988, there were 2 studies
published by Hutchinson et al. investigating the use of tizanidine plus ibuprofen or aspirin. In the
first, patients with acute low back pain were randomized to receive either ibuprofen plus
tizanidine, or ibuprofen plus placebo (10). Pain was assessed at 3 and 7 days. It was found that
both groups had effective treatment of symptoms, but patients receiving tizanidine reported
earlier resolution of symptoms. There was a significant improvement in pain control in the
tizanidine group compared to placebo especially in those patients with moderate to severe pain at
night, at rest, and in those with severe sciatica. It was also noted that those patients taking
tizanidine had significantly fewer gastrointestinal adverse events compared to those taking
ibuprofen alone. In the second study, patients were randomized to receive either tizanidine or
placebo (11). They were also given aspirin 300 mg to use as rescue medication. It was found that
in the tizanidine group, the consumption of aspirin was half that compared to the placebo group.
Pain at night, pain at rest, and restriction of movement were better controlled in the tizanidine
group compared to placebo. It was again noted that there were fewer gastrointestinal adverse
events in the tizanidine group compared to the placebo group. This is in keeping with animal
model research showing that tizanidine mediates gastric mucosal protection against anti-
inflammatory drugs. In 2009, Pareek et al. evaluated tizanidine in combination with aceclofenac
(NSAID) vs. aceclofenac alone in the treatment of acute low back pain associated with
radiographically proven degenerative lumbo-sacral spinal disorders (12). They found that adding
tizanidine to the NSAID resulted in improved VAS pain scores, and decreased pain especially at
rest and at night. They also noted increased spinal mobility in the tizanidine group. In September
2016, there was a small randomized controlled trial of 70 patients undergoing elective
cholecystectomy. They were randomized to receive either tizanidine or placebo 90 minutes prior
to surgery. In the tizanidine group, patients required much less postoperative narcotic medication
and had shorter recovery room stay compared to placebo. Tizanidine associated adverse effects
include hypotension, sedation, and dry mouth. It has also been associated with hepatotoxicity.
Hepatic function should be checked, and it should be avoided in patients with impaired hepatic
function. Withdrawal and rebound hypertension can occur; therefore, it should be tapered in
those patients who have taken tizanidine for long periods of time.

Benzodiazepines
Benzodiazepines,such as diazepam, function as agonists of the GABA-activated chloride
channel within the central nervous system. This results in sedation, anxiolysis, anticonvulsant,
and muscle relaxing properties. As reported in a 2003 Cochrane database review, there have been
several studies evaluating benzodiazepines in the management of acute and chronic low back
pain (13). For acute low back pain, they reported limited evidence that benzodiazepine treatment
was superior to placebo for short term pain relief, and better overall improvement, but it was
noted that there were a substantial number of central nervous system side effects including
dizziness, drowsiness, and confusion. In the treatment of chronic low back pain, there was strong
evidence that benzodiazepines were more effective than placebo for short term pain relief and
overall improvement compared to placebo (14). In direct comparison with other muscle
relaxants, diazepam was found in one small high quality trial to be inferior to carisoprodol for
treatment of muscle spasm. In a separate small, but high quality trial, diazepam was found to be
equivalent to tizanidine for treatment of pain, muscle spasm, and functional status.
Efficacy and tolerability of muscle relaxants for low back pain

There is evidence that muscle relaxant drugs provide clinically significant pain relief in
the short term for acute (but not chronic) LBP. There is no evidence to support the use of
benzodiazepines in LBP. There is a paucity of evidence on long-term use, and effects on
disability for these classes of medicines. Strengths of this review include a comprehensive search
strategy and coverage of medicines which are widely used to manage LBP. The PEDro scale was
used to assess risk of bias because it has acceptably high clinimetric properties (Maher et al.,
2003; de Morton, 2009; Macedo et al., 2010), whereas limitations have been reported for the
Cochrane risk of bias scale (Hartling et al., 2009; Armijo-Olivo et al., 2012). Limitations of this
study include possible publication bias, as only studies published in peerreviewed journals were
included.This review evaluates muscle relaxants for LBP with treatment effect expressed as a
mean between group difference, with 95% CI, for pain outcomes on a 0–100 scale. This practice
is in line with previous research exploring the efficacy of opioid analgesics medications for LBP
(Abdel Shaheed et al., 2016). Previous reviews in the area have typically focused on p values; a
practice which does not assist readers to judge if the treatment effect is clinically worthwhile,
or appreciate the precision of the estimate of the treatment effect. The present review also
provides an update of the evidence, including RCTs which were published after the latest review
of muscle relaxants for low back pain. The findings are particularly significant given the paucity
of evidence around the efficacy of opioid analgesics for acute low back pain (Abdel Shaheed et
al., 2016). It also adds to existing knowledge around effects of treatments commonly used for
non-specific back pain and can therefore inform the clinical decision making of prescribers.
Current guidelines report that there is conflicting evidence as to whether muscle relaxants are
more effective than placebo for acute LBP (National Health and Medical Research Council,
2004). This review has shown that muscle relaxants do provide clinically significant pain relief
compared with placebo for acute LBP. The majority of guidelines recommend that muscle
relaxants either be avoided in acute LBP or considered only when an adequate trial of simple
analgesics and or combination opioid analgesics has been unsuccessful (National Health and
Medical Research Council, 2004). The present review would suggest it is appropriate to consider
brief treatment with a muscle relaxant ahead of combination or single ingredient opioid
analgesics, especially as there is a paucity of evidence around opioid analgesic for acute LBP
from placebo-controlled trials. The benefit on pain with muscle relaxants identified in this review
therefore challenges the notion that there should be strict prerequisites to their use in people with
acute LBP. Nevertheless, the review supports existing recommendations that treatment should be
very brief (<1–2 weeks) for an acute episode of LBP (Waddell et al., 1999) given the paucity of
evidence on longterm outcomes. Very few muscle relaxant trials reported on global recovery
outcomes, and the effects on disability, where reported in this review were small. It is possible
that the combination with non-pharmacological management strategies such as light physical
activity may have a synergistic effect and future research should focus on evaluating the benefits
of such an approach. The findings from this review must be balanced against the individual risks
of the muscle relaxants evaluated, as the adverse events outcomes reported were very limited.
For example thiocolchicoside, the muscle relaxant found to have greatest benefit on pain, now
has restrictions around its use (European Medical Agency, 2013) following claims that
aneuploidy – a rare complication affecting chromosomes in the body – is linked with the drug.
Previous systematic reviews (van Tulder et al., 1997, 2003) of muscle relaxants showed a
significant effect of tizanidine, cyclobenzaprine, dantrolene, carisoprodol, baclofen and
orphenadrine compared with placebo; however, not all of these trials met the eligibility criteria
for inclusion in the present review. A number of studies on cyclobenzaprine and tizanidine for
instance, reported pain relief (Bianchi, 1978; Nibbelink et al., 1978; Baratta, 1982; Baptista
et al., 1988; Corts Giner, 1989) and whilst these have shown statistically significant benefit
compared with placebo, this may not necessarily translate to clinically important effects. In the
present review, the pooled estimates from the three trials which evaluated tizanidine were not
clinically significant. Additionally, given the abuse potential and sedative effects of some muscle
relaxant drugs, such as carisoprodol (van Tulder et al., 2003), care must be taken in providing
recommendations for use based on statistical significance. Importantly, this review shows there
are insufficient outcomes data beyond the short term for any muscle relaxant drug to support
the long term, unmonitored use of these medicines. There was no eligible RCT evidence
supporting the efficacy of benzodiazepines in people with LBP yet paradoxically, diazepam – a
benzodiazepine with sedative properties (Chouinard, 2004) – is ranked among the most
commonly prescribed medications for back pain in Australia and the United States (National
Health and Medical Research Council, 2004; Australian Institute of Health and Welfare (AIHW),
2009). Future research should focus on evaluating the efficacy and safety of muscle relaxant
drugs in combination with physical activity and other non-pharmacological measures such as
heat wrap therapy, to see whether there could be synergistic effects on pain and disability
outcomes.

Conclusion
Muscle relaxant drugs do not provide clinically significant pain relief in the short term for
people with acute LBP. There was a paucity of evidence around the use of benzodiazepines for
LBP and effects of the three classes of medicines on disability. The present evidence does not
support the recommendation for prolonged use of any of these drugs in the management of
people with LBP.